Expression of urokinase-type plasminogen activator,its receptor,and its inhibitor in gastric adenocarcinoma tissues.

The plasminogen and plasmin system, which is mainly regulated by urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1), is generally believed to play a role in cancer invasion and metastasis. This study was conducted to investigate the role of uPA, uPAR and PAI-1 in the invasion and metastasis of gastric adenocarcinoma. The expression of mRNAs for uPA and PAI-1 was determined by Northern blot analysis in nine primary gastric cancer tissues, nine paired metastatic lymph nodes and normal gastric mucosa. The mRNA of uPA was not or faintly detected in normal mucosa, while the expression was increased in both primary gastric cancer tissues and metastatic lymph nodes to a similar degree. The mRNA expression for PAI-1 in the gastric cancer tissues was not different from that in the paired metastatic lymph nodes and normal mucosae. uPAR was determined by immunohistochemical staining, demonstrating that five (56%) and six (67%) out of nine primary gastric cancer tissues and nine paired metastatic lymph nodes were positive, respectively and the intensity was stronger in metastatic lymph nodes. The results support the concept that most gastric cancer cells may have an innately moderate level of uPA and uPAR, and that increase of uPAR expression can be considered to be closely associated with cancer invasion and metastasis.     

Plasminogen activator system, vascular endothelial growth factor, and colorectal cancer progression.

AIMS: To plasminogen activator system (PAS) consists of the plasminogen activators (urokinase (uPA) and tissue-type (tPA) plasminogen activators), the uPA receptor (uPAR), and the plasminogen activator inhibitors (PAI-1 and PAI-2). Plasminogen activators activate plasminogen to plasmin, which can break down extracellular matrix (ECM) components. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is involved in angiogenesis. VEGF has been shown to upregulate uPA and this may facilitate tumour angiogenesis further. METHODS: PAS components and VEGF were determined by enzyme linked immunosorbent assay (ELISA) in paired colorectal tumour and normal tissue (n = 50) and correlated with pathological staging. RESULTS: uPA, uPAR, PAI-1, and VEGF values were significantly higher in tumour tissue (for example, tumour uPA: median, 2.3 (range, 0.1-6.7) ng/mg protein v normal uPA: median, 0.2 (range, 0-2.6) ng/mg protein). tPA was significantly higher in normal mucosa and there was no difference in PAI-2. uPA, uPAR, PAI-1, and VEGF values significantly correlated with each other and with Dukes's staging (uPA in adenomas: median, 0.42 (range, 0.1-1.2) ng/mg protein; upA in Dukes's B tumours: median, 2.1 (range, 0.4-4.3) ng/mg protein; and uPA in Dukes's D tumours: median, 4.0 (range, 3.7-4.2) ng/mg protein) and lymphatic invasion. In addition PAI-1 also correlated with tumour size and differentiation. CONCLUSION: The involvement of the PAS and VEGF in colorectal cancer appears to be complex. uPA, uPAR, PAI-1, and VEGF were upregulated in tumour tissue and this correlated with Dukes's staging and lymphatic invasion.     

Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma

It has become more and more clear in recent decades that the plasminogen activation system, which includes urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor (PAI)-1 and PAI-2, plays a very important role in the aggressiveness of cancer. Using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), the expression of these four components of the uPA system was analyzed in 19 cases of hepatocellular carcinoma (HCC) and 18 cases of the adjacent non-cancer tissues which all had chronic active hepatitis with liver fibrosis or liver cirrhosis. Four cases of normal liver tissues, as controls for immunohistochemical stains, were obtained from the hepatectomized liver of patients with metastatic cancer in the liver. The positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical stains in cancer tissues were 78.9, 68.4, 57.9 and 31.6%, respectively. Positive signals were mainly distributed in the cytoplasm of the cancer and in stromal cells. Moreover, the strong stains were chiefly located in the invasive front of the cancer cells. No specific stain was detected in four cases of normal liver tissues. In ELISA, there were significant differences between cancer and non-cancer tissues in concentration of uPA, uPAR and PAI-1 (P < 0.0003, 0.0024 and 0.01, respectively), but there was no significant difference in that of PAI-2 (P = 0.37). These results suggest that uPA, uPAR and PAI-1 are related to invasion of HCC.     

Prognostic relevance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in gastric cancer

Expression of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) was evaluated in 125 surgically resected gastric cancers by immunohistochemical analysis. Tissue was stained immunohistochemically with a monoclonal antibody against human uPA and monoclonal antibodies against human PAI-1 and PAI-2. In addition, DNA ploidy patterns were determined by cytofluorometer after staining with propidium iodide. We found that 82 (66%) of the 125 gastric cancers expressed uPA as diffuse cytoplasmic staining, as intensely outlined luminal borders. PAI-1 expression was observed in 62 (50%) of 125 gastric cancer as a fine, diffuse and granular pattern in the cytoplasm. PAI-2 expression was observed in 65 (52%) of the 125 gastric cancers as a diffuse cytoplasmic staining. uPA-positive tumours showed a higher incidence of infiltration, lymph node metastasis and peritoneal dissemination than uPA-negative ones. Patients with uPA-positive tumours proved to have a significantly poorer prognosis than those with negative ones. PAI-1-negative tumours showed a higher incidence of liver metastasis and carried a poorer prognosis than PAI-1-positive ones. There was no significant correlation between uPA or PAI-1 expression and DNA ploidy patterns. Conversely, there was no significant relationship between PAI-2 expression and clinicopathological parameters and prognosis. According to the expression of uPA and PAI-1 status, groups of 19 uPA(–)/PAI-1(–), 44 uPA(+)/PAI-1(–), 23 uPA(–)/PAI-1(+) and 39 uPA(+)/PAI-1(+) were subdivided. Tumours with UPA(+)/PAI-1(–) had a significantly higher incidence of liver metastasis, lymph node metastasis and serosal invasion than the other groups of tumours. Patients with uPA(+)/PAI-1(–) tumours had a significantly poorer prognosis than those with uPA(–)/PAI-1(+) tumours. These results indicate that uPA expression is a useful biological prognostic indicator, and that uPA and PAI-1 may play an important part in the tumour progression and metastasis in gastric cancer.     

uPA和PAI-1在人脑胶质瘤的表达及其与肿瘤血管生成的关系

目的探讨uPA、PAI鄄1和VEGF与人脑胶质瘤病理分级和侵袭行为的关系及各因子间的相互联系。方法采用免疫组化SP方法检测42例人脑胶质瘤和8例正常脑组织uPA、PAI鄄1和VEGF蛋白的表达。结果12例中低度恶性胶质瘤中,uPA、PAI鄄1和VEGF阳性表达率分别为58.3%、50.0%、33.3%,30例高度恶性胶质瘤的阳性率分别为96.7%、86.7%、93.3%,两组间各指标相比较,uPA和VEGF差异有极显著性(P<0.01),PAl鄄1差异有显著性(P<0.05)。uPA、PAI鄄1和VEGF阳性染色主要定位于血管内皮细胞和瘤细胞胞浆,以肿瘤侵袭边缘和坏死组织周围多见。uPA与VEGF、PAI鄄1与VEGF之间均呈明显正相关(P<0.05)。8例正常脑组织除1例有PAl鄄1微弱表达外,其余均为阴性。结论随脑胶质瘤恶性度增高,uPA、PAl鄄1和VEGF表达增强,三者协同作用,可作为胶质瘤恶性度高和侵袭能力强潜在的分子生物学指标。     

Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology

The urokinase-type plasminogen activator (uPA) system has been implicated in tumor spread. We have used immunohistochemistry to examine three components of this system, ie, uPA, uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in a pilot study on 142 cases of breast carcinoma. We wished to determine whether there were any relationships between expression of the proteins in either tumor cells or fibroblasts and clinical and pathological features. Strong uPA expression in each cell type was significantly related to high tumor grade (P = 0.013 and 0.008, respectively), and was more common in invasive than in in situ carcinomas (P < 0.0001). Fibroblastic expression of uPAR was only related to the presence of invasion (P < 0.0001). Strong PAI-1 expression in both cell types was seen in high-grade tumors (tumor cells, P = 0.012; fibroblasts, P < 0.001), but only fibroblastic expression was related to the presence of invasion (P = 0.042). Fibroblastic expression of both uPA and uPAR were positively correlated with tumor size. Although patients with strong fibroblastic expression of uPA showed a tendency toward a shorter time to relapse, none of the plasminogen activator proteins were significantly associated with relapse-free survival. These results suggest that strong expression of uPA, uPAR, and PAI-1 in fibroblasts rather than in tumor cells have the most impact on the clinical behavior of breast cancer. Larger prospective studies are needed to confirm these findings.     

胃癌组织中尿激酶型纤溶酶原激活剂及其受体基因表达和临床意义

目的：研究尿激酶型纤溶酶原激活剂（ｕＰＡ）及其特异受体（ｕＰＡＲ）与胃癌的关系及其在胃癌浸润转移中的作用。方法：采用ｃＤＮＡ－ｍＲＡＮ原位分子杂交技术,分别检测了６４例胃癌及其癌旁组织中ｕＰＡ和ｕＰＡＲｍＲＮＡ表达情况,同时结合病人的临床生物学指征进行分析。结果：癌与癌周比较,ｕＰＡ和ｕＰＡＲｍＲＮＡ阳性表达率明显升高,Ｐ〈０．００１。在伴有淋巴结转移的病例中,ｕＰＡ和ｕＰＡＲ阳性例数分别为１９／２９和２４／２９,与无转移的１０／３５和１３／３５相比,Ｐ分别〈０．０１和〈０．００１。在浸润到肌层、浆膜层的病例中ｕＰＡ和ｕＰＡＲ阳性例数分别为２５／３８和３０／３８,与浸润到粘膜和粘膜下层的４／２６例和７／２６相比,Ｐ均〈０．００１。在ｕＰＡ和ｕＰＡＲ同时阳性的病例中,伴有淋巴结转移和浸润到肌层以下的分别占１５／２     

Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer

The generation of urokinase plasminogen activator (uPA) by tumours is an important pathway for neoplastic cell invasion and metastasis. Indeed in several tumour types, elevated levels of uPA, its receptor (uPAR) or its inhibitor plasminogen activator inhibitor-1 (PAI-1) is associated with a poorer prognosis. Since endothelial cells also use this proteolytic system to remodel the extracellular matrix during angiogenesis and since angiogenesis, as assessed by microvessel density, is also a predictor of patient survival, this study was designed to investigate the relationship between angiogenesis and the urokinase system in breast tumours. The aims were to assess whether the uPA, uPAR and/or PAI-1 correlates with angiogenic activity and could therefore be a useful objective clinical measure of tumour neovascularization; and to clarify whether the poor outcome associated with high levels of the urokinase system is due to its association with angiogenesis. The study also sought to examine the relationship between the uPA system and vessel remodelling using loss of a basement membrane epitope (LH39) normally associated with established capillaries. The cytosolic levels of uPA, PAI-1 and uPAR were therefore measured by enzyme linked immunoabsorbent assay, together with tumour vascularity, in 136 well-characterized invasive breast carcinomas. There were significant relationships between uPA and uPAR (Spearman r=0.37, p<0.0001), uPA and PAI-1 (Spearman r=0.19, p=0.03) and between uPAR and PAI-1 (Spearman r=0.23 p=0.01). A significant correlation was also observed between PAI-1 and vessel remodelling (Spearman r=0.34, p=0.04), patient age (p=0.01), nodal status (p=0.047) and tumour grade (p=0.04), but no association between tumour vascularity and PAI (p=0.96), uPA (p=0.69) or uPAR (p=0.81) was present. No significant association was seen between any of the urokinase variables and expression of the angiogenic factor thymidine phosphorylase. Furthermore, no significant associations were found between any of the studied parameters and overall survival in a univariate analysis of the cancer patients. A multivariate Cox proportional hazard model of overall survival showed that uPA (p=0.15), but not uPAR (p=0.52) or PAI-1 (p=0.61), gave no additional prognostic information. These findings show that uPA may work via an independent pathway to angiogenesis and therefore combined blockade of uPA and angiogenesis may have additional therapeutic benefits. It also shows, as recently demonstrated in animal models, that PAI-1 may be a key regulator of vascular remodelling in human cancer.     

uPA系统与神经胶质瘤局部侵袭

uPA系统包括尿激酶型纤溶酶原激活物（urokinase plasminogen activator, uPA）、 尿激酶型纤溶酶原激活物受体（urokinase plasminogen activation receptor, uPAR）和纤溶酶原激活物抑制剂(plasminogen activator inhibitor, PAI),它们参与了多种人类恶性肿瘤的局部侵袭和转移,是目前肿瘤治疗重要的分子靶点。uPA能激活纤溶酶原降解细胞外基质与基底膜,uPAR则能显著提升uPA的激活纤溶酶原的功能,两者结合能够增强肿瘤的侵袭性与转移能力。PAI主要通过促进血管内皮生长因子（vascular endothelial growth factor,VEGF）的表达,促进新生血管的形成,从而促进肿瘤的局部侵袭,但PAI又可通过抑制uPA-uPAR复合体的生物学活性来抑制肿瘤的局部侵袭。神经胶质瘤是最常见的颅内肿瘤,很少转移到颅外,局部侵袭是其预后不良的主要原因。近年来发现uPA系统的表达水平与神经胶质瘤的恶性程度呈正相关。本文综述了uPA系统对神经胶质瘤局部侵袭的影响及其在治疗中的意义。     

Vitamin D3 modulation of plasminogen activator inhibitor type-1 in human breast carcinomas under organ culture

Urokinase plasminogen activator (uPA), its cell-bound receptor (uPAR) and its main inhibitor plasminogen activator type 1 (PAI-1) are present primarily in stromal cells in invasive breast carcinoma. The purpose of this study was to investigate the regulation by 1,25 dihydroxyvitamin-D3 (VD3) of these invasion-associated markers expressed in breast cancer tumors under organ culture, which preserves the interacting network of tumor and stromal cells. Breast carcinoma slices (30 cases), obtained using the Krumdieck tissue slicer, cultured for 48 h in the presence or absence of 100 nM vitamin D3, were embedded in formalin-fixed paraffin. uPA, uPAR, PAI-1 and VD3 receptor (VDR) were analyzed by immunohistochemistry, and their expression, detected in tumor cells and fibroblasts of the specimens, was not statistically changed by culture conditions. The proportion of cases expressing uPA, uPAR and PAI-1 was not affected by VD3 in epithelial cells, but the fraction of cases displaying strong PAI-1 reactivity in fibroblasts was reduced (P=0.016) compared with control slices. Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher VDR mRNA levels than epithelial cells. In cultured tumor fibroblasts, PAI-1 immunostaining and mRNA levels were reduced by VD3-limiting fibroblast contribution to invasion.     

Breast cancer: prognostic value of a dissemination index based on 4 components of the urokinase-type plasminogen activator system

Among the proteases involved in the tumor invasion process, components of the plasminogen activator system (plasminogen activator type-urokinase uPA, its membrane receptor uPAR and its two inhibitors PAI-1 and PAI-2) appear to define high risk patients in primary breast cancer. As individual analysis of each component of the plasminogen activator system does not reflect the complex interactions between the different components, we studied the prognostic impact of a dissemination risk index combining the four variables. We found that this index was the most powerful prognostic factor, particularly in node-negative patients.     

Spitz naevi may express components of the plasminogen activation system

The plasminogen activation (PA) system is involved in the process of invasion and metastasis. Its major components are urokinase (uPA) and tissue-type plasminogen activator (tPA), plasminogen activation inhibitor type 1 and 2 (PAI-1 and PAI-2) and a receptor for urokinase (uPAR). In this study, the expression of plasminogen activation components in Spitz naevi was compared with that in common and dysplastic naevi on the one hand and primary cutaneous melanomas on the other. Spitz naevi had melanocytic positivity for uPA in 0% (0/36), tPA in 30% (6/20), PAI-1 in 10% (3/35), PAI-2 in 40% (8/21) and uPAR in 60% (13/21) of cases. This far exceeded the expression found in common (n = 25) and dysplastic (n = 15) naevi, which only showed melanocytic positivity for PAI-2 (20% and 15% respectively) and in one dysplastic naevus also for uPAR. This was much (for most components significantly) less than the proportion of primary melanomas with tumour cell positivity, which was 30% (11/38) for uPA, 80% (19/24) for tPA, 75% (28/38) for PAI-1, 80% (19/24) for PAI-2 and 80% (19/24) for uPAR. The main findings of this study are that Spitz naevi, firstly, may express plasminogen activator (tPA), inhibitors and the receptor of the PA system, but in a much smaller proportion than cutaneous melanomas; and secondly, do not express urokinase, whereas some of the melanomas do. uPA positivity may therefore be suggestive of melanoma. However, overlapping staining results imply that the PA system has limited value in the differential diagnosis between Spitz naevus and primary melanoma. As serine protease components are expressed, Spitz naevi may use this proteolytic machinery to accomplish matrix degradation, although in a more restricted, possibly transient manner than melanomas.     

胃癌中uPA、PAI-1表达及其与血管生成的关系

目的 观察胃癌组织中uPA、PAI-1mRNA及蛋白的表达，并探讨它们与肿瘤分化、血管生成及临床病理因素之间的关系。方法 用原位杂交及免疫组化S-P法检测110例胃癌组织中uPA、PAI-1的表达，根据CD34阳性的血管内皮细胞计数肿瘤组织微血管密度（MVD）。结果 （1）胃癌组织中uPA mRNA和蛋白、PAI-1 mRNA和蛋白阳性表达定位于胞质；uPA的表达随分化程度的降低有逐渐升高的趋势，PAI-1的表达随分化程度的降低有逐渐降低的趋势。（2）110例uPA mRNA及蛋白表达阳性组MVD值显著高于阴性组，差异均具有显著性（P值均＜0．05）。（3）uPA mRNA及蛋白的表达与临床分期呈正相关（P＜0．05），PAI-1的表达与临床分期和淋巴结转移无相关性。（4）uPA mRNA／蛋白与PAI-1 mRNA／蛋白的表达无相关性。结论uPA与促进胃癌的血管生成密切相关，阻断uPA的分泌和作用途径有望对胃癌浸润转移起抑制作用；胃癌组织中PAI-1可能担当重要的调节剂或者是肿瘤细胞防止自身降解的保护剂而不是这个系统的单纯抑制剂。     

乳腺癌组织中uPA、uPAR及nm23-H1的表达

目的　观察乳腺癌组织中uPA、uPAR、nm2 3 H1的表达并探讨与腋窝淋巴结转移的关系。方法　用免疫组化EnVi sion两步法检测 6 9例乳腺癌组织中uPA、uPAR和nm2 3 H1表达的分布情况 ,观察其与肿瘤的分化程度以及与腋窝淋巴结转移的关系。结果　 (1)uPA阳性表达定位于癌细胞胞质 ;uPAR和nm2 3 H1阳性表达定位于癌细胞胞膜及胞质 ,多数癌旁乳腺上皮细胞呈nm2 3 H1阳性表达 ;高分化乳腺癌 (Ⅰ级 )uPA和uPAR表达阳性率 (30 0 %和 2 5 0 %)低于中低分化乳腺癌 (Ⅱ、Ⅲ级 ) (分别为 6 8 1%、72 7%和 70 0 %、74 1%) (P <0 0 5 ) ;nm2 3 H1表达阳性率在乳腺癌组织不同分化程度间差异无显著性 (P >0 0 5 ) ;(2 )腋窝淋巴结有转移者uPA和uPAR的表达阳性率 (73 2 %和 75 6 %)高于无淋巴结转移者 (35 7%和35 7%) (P <0 0 5 ) ;有腋窝淋巴结转移者nm2 3 H1的表达阳性率 (2 4 4 %)显著低于无淋巴结转移者 (5 0 0 %) (P <0 0 5 ) ;uPA、uPAR和nm2 3 H1的表达与淋巴结转移的个数均无关 ;(3)uPA阳性表达的癌组织其nm2 3 H1表达阳性率 (15 0 %)低于uPA阴性表达的癌组织 (6 2 1%) (P <0 0 5 )。结论　uPA和uPAR的高表达与乳腺癌腋窝淋巴结转移密切相关 ;uPA、uPAR和nm2 3 H1可以作为乳腺癌侵袭与淋巴结转移的     

Downregulation of uPAR confirms link in growth and metastasis of osteosarcoma

The uPA/uPAR system is involved in tumour progression and metastasis of a variety of cancers. Previously, we have shown that increased expression of urokinase plasminogen activator (uPA) correlated with malignancy grade in certain sarcomas. A study looking at in vivo inhibition of this system has not been done to date for osteosarcoma. More recently, this laboratory developed a clinically relevant mouse model where intratibial injection of UMR106-01 cells resulted in the development of osteosarcoma and lung metastases. Expression of uPA and its receptor (uPAR) were localised to the invading front of the tumours. Pulmonary metastasis is a predominant feature of the disease and is the major cause of death in patients. In the present study, the effects of down-regulating uPAR were observed in vitro and in vivo. UMR106-01 cells were transfected with either antisense-uPAR or vector control plasmids. Two antisense clones, exhibiting uPAR downregulation, demonstrated decreased adhesion, migration and invasion in cell-based assays in vitro (P<0.05). Cellular proliferation was not affected by uPAR downregulation. In␣vivo, a marked reduction of 80% in tibial tumour volumes (P<0.05), and total inhibition of pulmonary metastases were observed in mice injected with the more potent of the antisense clones. This study proves seminally the usefulness of uPAR antisense in curbing the growth and spread of osteosarcoma.     

Markers of the uPA system and common prognostic factors in breast cancer

The urokinase plasminogen activator (uPA) system includes uPA and plasminogen activator inhibitor types 1 (PAI-1) and 2 that mainly act by regulating extracellular matrix degradation, and it is involved in tumor progression. The -675 4G/5G polymorphism of the PAI-1 gene regulates PAI-1 activity in serum. We aimed at studying the -675 4G/5G polymorphism of the PAI-1 gene and uPA, PAI-1, and cyclooxygenase-2 (COX-2) immunohistochemical expression in a series of breast cancer cases. Homozygosity for the 4G allele of the PAI-1 gene was associated with node-positive breast cancer ( P = .02). We showed a direct correlation between uPA and estrogen receptor expression ( P = .03); negative uPA expression was associated with negative hormonal expression, high tumor grade, and high proliferation index ( P < .05). A direct correlation was seen between uPA and PAI-1, uPA and COX-2, and PAI-1 and COX-2 expression ( P < .05). Interaction between uPA and COX-2 systems in breast cancer deserves further study.     

大鼠肝纤维化过程中4种肝脏细胞对纤溶系统的调节

目的:探讨在大鼠肝纤维化发展过程中,肝细胞、肝星状细胞(HSCs)、Kupffer细胞和内皮细胞(ECs)对纤溶系统的调节作用。方法:采用1周2次皮下注射50%CCl4、持续12周的方法制备大鼠慢性肝纤维化模型;将肝纤维化不同时期的4种肝脏细胞进行分离;采用Northern印迹法及Western印迹法分别测定大鼠各类肝脏细胞中尿激酶型纤溶酶原激活物(uPA)、以及它的抑制物(PAI-1)和受体(uPAR)的mRNA和蛋白表达。结果:Northern印迹法及Western印迹法分析均显示,在大鼠肝纤维化过程中,HSCs和ECs均为PAI-1、uPAR的主要产生细胞,相比之下,HSCs产生更多。结论:在大鼠肝纤维化发生发展过程中,HSCs和ECs对纤溶系统成分的产生起着重要的调节作用,而HSCs则是PAI-1、uPAR最主要的产生细胞。     

The plasminogen activator inhibitor "paradox" in cancer

Proteolysis in general and specifically the plasminogen activating system regulated by urokinase (uPA) its specific receptor, the GPI membrane anchored urokinase receptor (uPAR) and the specific plasminogen activator inhibitor 1 (PAI-1) plays a major role in tumorigenesis, tumor progression, tumor invasion and metastasis formation. This is exemplified by a body of published work showing a positive correlation between the expression of uPA or uPAR in several tumors and their malignancy. It is generally assumed that such a "pro-malignant" effect of the uPA-uPAR system is mediated by increased local proteolysis thus favoring tumor invasion, by a pro-angiogenic effect of this system and also by uPA-uPAR signaling towards the tumor thereby shifting the tumor phenotype to a more "malignant" one. However, when tumor patients are analyzed for long term survival, those with high levels of the inhibitor of the system, PAI-1 have a much worse prognosis than those with lower PAI-1 levels. This indicates that increased overall proteolysis alone cannot be made responsible for the adverse effects of the plasminogen activating system in tumors. Moreover, it becomes increasingly evident that components of the fibrinolytic system secreted by the tumor cells themselves are not solely responsible for a correlation between the plasminogen activating system and tumor malignancy; components of the plasminogen activating system secreted by stroma cells or cells of the immune system such as macrophages contribute also to the impact of fibrinolysis on malignancy. This review summarizes the evidence for the role of plasminogen activator inhibitor-1 in mediating the malignant phenotype and possible mechanism thereby trying to explain the "PAI-1 paradox in cancer" on a molecular level.     

急慢性乙型肝炎患者血浆uPA和uPAR的检测及意义

目的研究急慢性乙型肝炎uPA和uPAR的表达，探讨肝炎发病时血液纤溶的变化及意义。方法应用酶联免疫吸附试验（ELISA）测定血浆uPA和uPAR的水平。结果急慢性乙型肝炎血浆uPA和uPAR水平与对照组比较均有意义地高于对照组（P〈0．01）；慢性乙型肝炎重度组血浆uPA和uPAR水平显著高于急性乙型肝炎组（P〈0．05），亦显著高于慢性乙型肝炎中轻度组（P〈0．05和P〈0．01）；急性乙型肝炎血浆中uPAR水平显著高于慢性乙型肝炎中轻度组（P〈0．01）；乙型肝炎急性期血浆中uPA和uPAR水平显著升高，恢复期明显回落（P〈0．05和P〈0．01），但仍明显高于正常对照组（P〈0．01）；急慢性乙型肝炎血浆中uPAR水平与凝血酶原时间（PT）（r=0．605，P〈0．01）和国际标准化比率INR（r=0．603，P〈0．01）、胆红素（TB）（r=0．649P〈0．01）呈正相关。结论急慢性乙型肝炎uPA和uPAR水平的升高，与炎症的严重程度有关，与肝细胞损伤程度有关，是肝炎发病时血液凝血和纤溶系统失衡的重要原因之一。     

The urokinase-type plasminogen activator and inhibitors in resectable lung adenocarcinoma

BackgroundThe urokinase-type plasminogen activator (uPA) system is closely related to the occurrence and progression of cancer in many aspects. Previous studies demonstrated that the conclusions about the prognosis value of uPA, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) in lung cancer are controversial, so this study was performed for the exploration of the predictive effect of uPA, PAI-1 and PAI-2 on the overall survival (OS) of resectable pulmonary adenocarcinoma patients.MethodsUPA, PAI-1 and PAI-2 expression levels were assayed by immunohistochemical staining based on tissue microarray (TMA) that is composed of formalin-fixed paraffin-embedded specimens from 84 resectable lung adenocarcinoma patients from July 2004 to June 2009. The relationship of IHC, mRNA expression levels of three molecules were investigated respectively. The three molecules’ relationship with clinicopathologic parameters and OS was explored by Chi-square, Kaplan-Meier, and Cox regression analyses. The Cancer Genome Atlas (TCGA) database was used to analyze differential gene expressions of RNA-sequencing data of pulmonary adenocarcinoma and normal tissues, and Kaplan-Meier methods were adopted to confirm the prognostic value of uPA, PAI-1 and PAI-2 in resectable lung adenocarcinoma in TCGA database and the R package MethylMix was used to conduct an analysis integrating methylation data and gene expression of RNA-sequencing data based on TCGA.ResultsUPA, PAI-1 and PAI-2 had much higher IHC expression levels in tumor than those in the normal tissues (uPA, Z = -10.511; PAI-1, Z = -4.836; PAI-2, Z = -6.794; all P < 0.0001). High DNA methylation level of gene uPA resulted in the decrease of its expression. In addition, expression level of PAI-2 was positively associated with tumor size (χ² = 8.372, P = 0.004). Multivariate analyses showed TNM stage III was an independent adverse prognostic factor (hazard ratio = 3.736, 95 % confidence interval = 1.097–12.72, P = 0.035). Kaplan-Meier method revealed that uPA, PAI-1 and PAI-2 expression levels were not related to the OS for 84 resectable lung adenocarcinoma patients. According to TCGA data, PAI-1 expression level was identified as a potential adverse predictor for prognosis of resectable lung adenocarcinoma (Gehan-Breslow-Wilcoxon test, P = 0.025).ConclusionsOur data show that, the expression levels of uPA, PAI-1 and PAI-2 are significantly up-regulated in resectable lung adenocarcinoma. Besides, this study highlights PAI-1 as a latent adverse prognostic factor in resectable adenocarcinoma of lung.